During retinal development, neuroepithelial progenitor cells switch from a symmetric proliferative mode, where both daughter cells remain in the mitotic cycle, to a neurogenic mode, where at least one of the daughter cells exits the cell cycle and differentiates as a neuron (or later as a glial cell). The cellular mechanisms that promote neurogenic divisions in the vertebrate nervous system remain unknown. Several recent observations demonstrate a fundamental role for interkinetic nuclear migration (IKNM) and polarized signals in regulating neurogenesis within the retina. IKNM is the process in which neuroepithelial nuclei oscillate from the apical to basal surface in phase with the mitotic cycle. We will investigate how specific phases of the cell cycle and the apical-basal position of the nucleus in progenitor cells impact the selection of neurogenic cell divisions and ultimately facilitate normal retinal lamination. In our studies, we will also investigate the influence of polarized signals during retinogenesis. This research will provide fundamental insights into signal integration and cell-fate commitment of retinal progenitor cells. Because of the fundamental nature of this research, our results have relevance to both retinal stem cell manipulation and disease processes. PUBLIC HEALTH RELEVANCE: This proposal outlines experiments to understand the mechanisms for how progenitor cells are selected to generate neurons. Fundamental knowledge of this process is important for guiding further research on stem cell biology, regenerative medicine, and retinal disease. [unreadable] [unreadable] [unreadable]